2008 Grants - Galvan

Small-Molecule Inhibitors of Asp664 Cleavage of APP

2008 New Investigator Research Grant

The protein fragment beta-amyloid is thought to disrupt cell-to-cell communication and cause brain cell death in Alzheimer's disease. Accumulations of beta-amyloid are a hallmark of the Alzheimer brain. Yet this protein fragment also occurs in the brains of healthy people, and scientists do not know exactly how beta-amyloid becomes toxic in certain brains and remains benign in other brains.

Beta-amyloid is clipped from its parent molecule, amyloid precursor protein (APP). APP is a transmembrane protein that exists partially inside a brain cell and partially outside the cell. Veronica Galvan, Ph.D., and colleagues have found that when APP is clipped at Asp664, a region of the protein that exists inside a cell, this cleavage may lead to the production of toxic beta-amyloid. The researchers analyzed mice engineered to produce both beta-amyloid and mutated Asp664 regions. Results showed that these mice developed amyloid clumps without sustaining Alzheimer-related cognitive deficits.

Dr. Galvan's team also determined that an enzyme called caspase-8 was involved in clipping APP at its Asp664 region. Thus the researchers hypothesize that by blocking caspase-8/Asp664 interactions, they can mediate the production of toxic beta-amyloid.

For this study, Dr. Galvan and colleagues will use sophisticated screening techniques to search for molecules that can prevent caspase-8/Asp664 interactions in cultured cells. Their search will screen about 150,000 molecules at Harvard University's Laboratory for Drug Discovery in Neurodegeneration Library.

The results of this effort could identify novel drugs that inhibit beta-amyloid toxicity and prevent or slow the progression of Alzheimer's disease. The study could also shed new light on biological mechanisms underlying Alzheimer's.